The discussion that follows is intended solely as background information to assist in the understanding of this invention; nothing in this section is intended to be, nor is it to be construed as, prior art to the invention.
In the early 1980's, the utility of implantable medical devices, which had been in use by the medical community for about 30 years, was expanded to include localized delivery of drugs. It was found that implantable devices could be fabricated with drugs incorporated directly into their structure or, more commonly, incorporated in a coating adhered to a surface of the device. In either case, the drug was shielded from the environment until the device was delivered to and released at the treatment site. The advantages of localized drug delivery are manifest.
Site specific delivery permits the establishment of a high local concentration of a drug with concomitant low level systemic exposure and less potential for undesirable side effects. Thus, for example, the hemorrhagic complications that can accompany systemic delivery of an antithrombotic agent can be avoided. Likewise, the pervasive toxicity of antineoplastics to all living cells can be focused on malignant cells only by delivery of the drug at or into a tumor. Localized delivery also permits use of drugs that, for one reason or another, are not amenable to delivery by other means. This includes drugs that, for instance, are susceptible to degradation under physiological conditions and therefore would biodegrade before reaching the treatment site if administered systemically and drugs that are substantially insoluble in physiological solution, which is primarily aqueous, such that they precipitate and are immobilized almost immediately on administration.
Of course, the ability to use less of a drug using localized delivery can also constitute a substantial economic benefit.
One technique for the localized delivery of drugs involves dispersion of the drug in a polymeric carrier to create a “drug reservoir” from which the drug can be delivered once situated at a treatment site. A drug reservoir polymer must be biocompatible, that is, its intact, as-synthesized state and its degradation products, if it decomposes to any substantial degree, must not be, or at least should minimally be, toxic or otherwise injurious to living tissue. Furthermore, the polymer or its degradation products should not, or again should at least minimally and/or controllably, cause an immunological reaction in living tissue.
An area of on-going research regarding localized drug delivery is control of a drug release profile. The physical and chemical properties of the polymer employed as the drug reservoir in large part controls the release profile of a drug dispersed in it. For instance, if the drug reservoir polymer is durable, that is if it is stable in a physiological environment and does not biodegrade to any substantial degree, then the predominant mechanism by which a drug will escape the reservoir is by simple passive diffusion from the polymer matrix, with or without prior swelling of the polymer due to exposure to bodily fluids. The drug release profile achieved by passive diffusion may not, however, be optimal. Conditions such as whether or not the reservoir polymer is cross-linked, and if so the structure of the cross-linked matrix, in particular the size of pores and the tortuousness of the path the drug must take to arrive at the surface of the polymer will affect the release profile. The physical dimensions of the drug itself, as well the geometry of the implantable device and the geometry of the reservoir layer will also impact the release profile. For example, release from a thin layer of polymer coated on a device may differ substantially from the release from microspheres or nanospheres adhered to the surface of the device. The thickness or, in the case of a sphere, the average diameter, of the reservoir will also affect drug release.
An alternative to using durable polymers as the drug reservoir is using biodegradable polymers. While a host of parameters such as molecular weight, molecular weight distribution, sterilization history, shape, annealing, processing conditions, presence of ionic groups, configurational structure, etc, contribute to determining a polymeros degradation characteristics, a primary factor that determines biodegradability is chemical composition. That is, biodegradable polymers have functional linking groups bonding the monomers together that are selected so as to be susceptible to biodegradation in vivo. The degradation is often enzyme-catalyzed, but may also be affected by other physiological factors such as pH. Biodegradable polymers can be divided into two general types, surface-eroding and bulk-eroding.
Surface-eroding polymers tend to be hydrophobic, causing mass loss at the polymer surface to be greater than mass loss caused by ingress of water into the polymer bulk. Surface erosion generally occurs at a controlled, predictable rate. Thus, a drug contained within the polymer matrix is released at a constant rate as erosion progresses, provided that the exposed surface area of the polymer does not change. Surface-eroding polymers include polyanhydrides, polyorthoesters and polyketals. With the exception of polyketals, the degradation products of these polymers include acids. Since this degradation can be acid-catalyzed as well an enzyme-catalyzed, auto-catalysis may occur.
Autocatalysis occurs when the degradation products of a polymer themselves are capable of catalyzing further degradation of the polymer. The subsequent build-up of more and more catalyst causes an escalating degradation rate. In the case of surface-eroding polymers, however, the phenomenon does not usually occur because the acidic degradation products are rapidly washed away from the surface of the polymer and are not present in high enough concentration to substantially autocatalyze further degradation.
The degradation products of surface-eroding polymers, like any polymer intended for use in vivo, must be biocompatible. While a number of such polymers are known and have found use in implantable medical devices used for the controlled drug release of therapeutic agents, in general their degradation products are rarely totally innocuous and their use must generally be carefully monitored.
On the other hand, polylactides, polyglycolides and co-polymers thereof are largely innocuous in vivo. They have been used in vivo for over 20 years beginning with biodegradable sutures. Their popularity stems from the fact that their degradation products, lactic acid and glycolic acid, are naturally-occurring compounds that, upon formation in vivo, are capable of entering into the Krebs cycle and thereafter being converted to carbon dioxide and water. Thus, these polymer and their degradation products place little or no additional stress on a patient's often already compromised physiological state. Polylactides and polyglycolides are, however, bulk-eroding polymers.
Bulk-eroding biodegradable polymers tend to be hydrophilic, that is, water compatible. These water compatible polymers absorb water and along with it the enzymes and other biodegradation-causing components of a physiological system. The absorbed components cause internal degradation of the polymer at a rate that competes with the rate of surface erosion. That is, degradation takes place simultaneously throughout the polymer matrix. The result can be an extremely complex drug release profile as differential degradation takes place in the bulk of the polymer and drug is released from throughout the polymer matrix in a haphazard manner. Rather than a smooth, linear release profile such as that obtained with surface-eroding polymers, burst releases of massive amounts of drug, which can be detrimental to the health and safety of the patient, may occur. Autocatalysis compounds this situation for polyesters such as polylactides and polyglycolides. Unlike surface-eroding polymers, when bulk-eroding polymers degrade to their component acids, the acids remain trapped for an extended period of time within the remaining polymer matrix wherein they catalyze further degradation, which further complicates the release profile of an incorporated therapeutic agent.
A method of manipulating bulk-eroding polymers such that in use they exhibit surface erosion characteristics rather than bulk erosion characteristics would be desirable. The present invention provides such a method.